WO2005094826A1

WO2005094826A1 - Anti-itching agent

Info

Publication number: WO2005094826A1
Application number: PCT/JP2005/006015
Authority: WO
Inventors: Naoki Izumimoto; Toshikazu Komagata; Toshiyuki Honda; Koji Kawai
Original assignee: Toray Industries, Inc.
Priority date: 2004-03-30
Filing date: 2005-03-30
Publication date: 2005-10-13
Also published as: CN100586434C; EP1736157A1; ATE414516T1; US7718664B2; CA2561509C; US20080275074A1; EP1736157A4; CN1938028A; KR101233289B1; JP4882744B2; CA2561509A1; TW200533355A; JPWO2005094826A1; EP1736157B1; KR20060132953A; ES2317219T3; PT1736157E; DE602005011113D1

Abstract

A novel anti-itching agent useful for the treatment of itches accompanying various diseases. The anti-itching agent contains as an active ingredient a morphinan derivative having a specific nitrogenous cyclic substituent or a pharmacologically acceptable acid addition salt thereof, such as, e.g., N-(17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl)phthalimide hydrochloride, [Chemical formula 1] (1) or N-(17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl)-3,4,5,6-tetrahydrophthalimide tartrate.

Description

Specification

Antipruritic

Technical field

The present invention relates to an antipruritic comprising a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof as an active ingredient, which is useful for treating itch associated with various diseases. .

Background art

[0002] Itching (pruritus) is known to be expressed in various skin diseases accompanied by inflammation, and also to be perceived for medical diseases, pregnancy, parasitic infection, and sometimes for drug or psychogenic reasons. I have. It is an area where research has been delayed due to difficulties in quantitative and objective evaluation, and the mechanism of the development of itch has not yet been fully elucidated. Histamine, substance P, bradykinin, proteinase, prostaglandin, opioid peptide, and the like.

Hitherto, antihistamines, antiallergic agents, etc. have been mainly used as inner β agents for the treatment of pruritus, and external agents such as antihistamines, corticosteroids, non-steroid anti-inflammatory agents, Menthol, phenol, salicylic acid, tar, crotamiton, capsaicin and humectants (urea, hirudoid, petrolatum, etc.) have been used. However, in the case of oral medications, there are problems such as the time required for onset of action, side effects of the central nervous system (drowsiness, malaise), and problems with the digestive system. On the other hand, in the case of topical preparations, the antipruritic effect is not sufficient. Local side effects such as become a problem!

[0004] By the way, as a finding indicating the relationship between a compound having a morphinan skeleton and pruritus, when morphine is administered intraepithelial or intrathecally, itching is induced contrary to the compound used in the present invention. (Non-Patent Document 1). On the other hand, the pruritus induced by intrathecal administration of morphine was suppressed by naloxone, an opioid antagonist (Non-patent Document 2), and the strong pruritus induced by cholestatic patients with hepatic impairment was Opioid antagonist (Non-Patent Document 3) has also been reported. Further, a 6-chain-chain-substituted morphinan compound having an antipruritic effect and represented by the following general formula is disclosed (Patent Document 1).

[0005] [Formula 1]

[0006] On the other hand, morphinan compounds having a nitrogen-containing cyclic substituent are described in Non-Patent Documents 2 and 3, but are disclosed only for analgesics and antitussives (Patent Documents 2 and 3). ), Non-patent Documents 4, 5, and 6 only describe compounds, but especially for use V, and no description! ヽ (Non-patent Documents 4, 5, and 6) (Polituria 'urinary incontinence) The use of a therapeutic agent is disclosed later than the priority date of the present application (Patent Document 4). However, the compound has a nitrogen-containing cyclic substituent at the 6-position of the morphinan structure, which has a certain link between the structure and pharmacological activity of the compound via the obioid receptor and the antipruritic effect according to the present invention. No remarkable and useful antipruritic effect of the antipruritic agent of the present invention is analogized.

[0007] Non-Patent Document 1: J. H. Jaffe and W. R. Martin, Goodman and Gilman's Pharmacological Basis of Therapeutics, Macmillan, New York, 1985

Non-Patent Document 2: J. Bernstein et al, J. Invest. Dermatol, 78, 82-83, 1982

Non-Patent Document 3: J.R.Thornton and M.S.Losowsky, Br.Med.J "297, 1501-1504, 1988

Non-Patent Document 4: C. Simon et al., Tetrahedron, 50, 9757-9768, 1994

Non-Patent Document 5: C. Simon et al "Synth. Commun" 22, 913-921, 1992

Non-Patent Document 6: LM Sayre et al "J. Med. Chem., 27, 1325-1335, 1984

Patent Document 1: International Publication WO 98/23290

Patent Document 2: JP-B-41 18824

Patent Document 3: JP-B-41-18826 Patent Document 4: International Publication WO 04/33457

Disclosure of the invention

Problems to be solved by the invention

[0008] It is an object of the present invention to provide a novel antipruritic agent useful for treating itch associated with various diseases.

Means for solving the problem

As a result of intensive studies to achieve the above object, the present inventors have found that a compound having a nitrogen-containing cyclic substituent at a specific position of the morphinan structure has an excellent therapeutic effect on pruritus and has few side effects. Completed the invention.

That is, the present invention provides a compound represented by the general formula (I)

[0011] [Formula 2]

Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkylalkyl having 6 to 8 carbons, aryl having 6 to 12 carbons, carbon Aralkyl having 7 to 13 carbon atoms, alkaryl having 3 to 7 carbon atoms, fulleralkyl (alkyl portion has 1 to 5 carbon atoms), chenylalkyl (alkyl portion has 1 to 5 carbon atoms), or pyridylalkyl (The alkyl moiety represents 1 to 5);

R ² and R ³ are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, alkoxy-alkoxy having 3 to 7 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or alkyl having 1 to 5 carbon atoms. Represents canoiloxy;

Υ, Ζ independently represent a valence bond or -C (= 0) _;

-X- is a carbon chain of 2 to 7 carbon atoms that becomes part of the ring structure (unsaturated in carbon chains in which one or more carbon atoms may be replaced by nitrogen, oxygen, or sulfur atoms) Conclusion , Which may be included)

k represents an integer from 0 to 8;

R ⁴ is k substituents on the nitrogen-containing cyclic structure, each of which is independently fluorine, chlorine, bromine, iodine, nitro, hydroxy, alkyl having 1 to 5 carbons, cycloalkylalkyl having 7 to 13 carbons, Aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, isothiocyanato, SR ⁶ , SOR ⁶ , SO R ⁶ , (CH) OR ⁶ , (CH) COR ⁶ , (CH)

2 2 p 2 p 2 p

K R ^{4 s} force representing COR ⁶ , SO NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH) NR ⁷ R ⁸ , (CH) N (R ⁷ ) COR ⁸

2 2 2 p 2 p

Chi, the same two R ⁴ an oxygen atom and is carbonyl group or a sulfoxide group Ghats attached to a carbon atom or a sulfur atom, and two R ⁴ Ghats sulfur atoms attached to the same carbon atom Two thiocarbonyl groups are substituted by four R ⁴ forces ^ oxygen atoms bonded to the same sulfur atom to represent a sulfone group, or substituted by adjacent carbons among k R ⁴ Benzene condensed ring, pyridine condensed ring, naphthalene condensed ring, cyclopropane condensed ring, cyclobutane condensed ring, cyclopentane condensed ring, cyclopentane condensed ring, unsubstituted or substituted with one or more substituents R ⁵ together with R ⁴ Represents a condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring, and R ⁵ is each independently fluorine, chlorine, bromine, iodine, nitro, , Hydroxy, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, trifluoromethyl, trifluoromethoxy, siryl having 6 to 12 carbons, isothiocyanato, SR ⁶ , SOR ⁶ , SOR ⁶ , (CH) 0R ⁶ , (CH

2 2 p

) COR ^6, represent ^{(CH) CO R 6, SO} NR 7 R 8, CONR 7 R 8, (CH) NR 7 R 8, (CH) N (R 7) COR 8

2 p 2 p 2 2 2 p 2 p

R ⁹ is hydrogen, alkyl having 1 to 5 carbons, alkaryl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, hydroxyalkyl having 1 to 3 carbons, (CH) OR ⁶ , or (CH ) COR ⁶

2p2p2 represents;

R ^1Q and R ¹¹ are combined to represent -0-, -S-, or ^-CH- , or R ^1Q is hydrogen and R ¹¹ is water

2

Represents hydrogen, hydroxy, alkoxy having 1 to 5 carbons, or alkanoyloxy having 1 to 5 carbons;

p represents an integer from 0 to 5; R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, alkyl having 3 to 7 carbons, aryl having 6 to 12 carbons, or aralkyl having 7 to 13 carbons;

RR ⁸ independently represents hydrogen, alkyl having 1 to 5 carbons, or aralkyl having 7 to 13 carbons, and the general formula (I) includes a (+) form, a (-) form, and a (f) form And a pharmaceutically acceptable acid addition salt thereof as an active ingredient. The present invention also relates to the use of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the above general formula (I) or a pharmacologically acceptable caro salt with an acid for the production of an antipruritic. provide. Further, the present invention provides a method for administering to a patient an effective amount of one or more of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the above general formula (I) and a pharmacologically acceptable acid addition salt thereof. A method of pruritus, comprising:

The invention's effect

The antipruritic agent of the present invention has an excellent antipruritic effect and has few side effects.

BEST MODE FOR CARRYING OUT THE INVENTION

[0014] As described above, the antipruritic agent of the present invention comprises, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof. Containing. The antipruritic agent of the present invention comprises an active ingredient selected from the group consisting of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) and a pharmacologically acceptable acid addition salt thereof alone. May be included, or may be included in combination of two or more.

[0015] Among the compounds represented by the general formula (I), in the general formula (I), those in which Y is -C (= 0)-are particularly preferable. Particularly, both Υ and Ζ are -C (= 0)-is preferred.

[0016] R ¹ is preferably hydrogen, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkylalkyl having 6 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, or arylalkyl having 3 to 7 carbon atoms. Hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutenylmethyl, 2-cyclobutenyl Preference is given to tyl, 3-cyclobutenylpropyl, phenol, naphthyl, tolyl, aryl, 3-butul and propyl. these Among them, hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, aryl and propyl, particularly hydrogen, cyclopropylmethyl, cyclobutylmethyl and aryl are preferred.

[0017] R ² and R ³ are hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons. Among them, hydrogen, hydroxy, methoxy, ethoxy, aryloxy, benzyloxy, acetoxy or propionoxy are preferred. Among these, hydrogen, hydroxy, methoxy and acetoxy are particularly preferred.

[0018] -X- is a carbon chain having 2 to 4 carbon atoms which becomes a part of the ring structure (however, one of the carbon atoms may be replaced by a sulfur atom, and the carbon chain may contain an unsaturated bond. However, it is preferable that the carbon chain be a carbon chain having 2 carbon atoms which becomes a part of the ring structure.

[0019] Preferably, k is an integer from 0 to 6! /.

[0020] R ⁴ is alkyl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, aralkyloxy having 7 to 13 carbons, or four R ⁴力 bonded to the same sulfur atom. A benzene condensed ring, a pyridine condensed ring, or a naphthalene ring, in which a sulfone group serving as an oxygen atom, and further R ² substituted on two adjacent carbons are joined together to be unsubstituted or substituted by one or more substituents R ⁵ It is preferable to form a condensed ring, a cyclopropane condensed ring, a cyclobutane condensed ring, a cyclopentane condensed ring, a cyclopentene condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring. . Among them, methyl, ethyl, ethylidene, propyl, propylidene, butyl, butylidene, benzyl, benzylidene, methylbenzyl, methylbenzylidene, fluorobenzyl, fluorobenzylidene, trifluoromethoxybenzyl, trifluoromethoxybenzylidene, phenethyl, phenethylidene, cycloalkyl Preference is given to the formation of a hexylmethyl, cyclohexylmethylidene, phenoxy, chlorophenoxy, sulfone group or to the formation of a fused benzene or cyclohexene ring, in particular two unsubstituted R ^{4 taken} together Alternatively, it is preferable to form a benzene condensed ring or a cyclohexene condensed ring substituted with one or more, particularly 1 to 4 substituents R ⁵ . In this case, four R ⁴ forces bonded to the same sulfur atom スルホン U, which also preferably form separately. The unsubstituted benzene-fused ring or cyclohexene-fused ring is also preferably unsubstituted. However, as the substituent R ⁵ , fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbons (particularly methyl, ethyl) , Propyl), aralkyl having 7 to 13 carbon atoms (especially benzyl), hydroxy, alkoxy having 1 to 5 carbon atoms (especially methoxy, ethoxy), trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanate, SR ^{^{^{6, SOR 6, SO R 6}}} , (CH) OR 6, (CH) COR 6, (CH) CO R 6, SO NR 7 R 8, CONR 7 R 8

2 p 2 p 2 p 2 2

, (CH (R ⁷ ) COR ⁸ (where p represents an integer of 0 to 5, R ⁶ is hydrogen, carbon

Represents an alkyl of 1 to 5 (especially methyl, ethyl, propyl), an alkyl of 3 to 7 carbons or an aryl of 6 to 12 carbons (especially phenol),

R ⁸ is preferably independently hydrogen, alkyl having 1 to 5 carbons (especially methyl, ethyl, propyl) or aralkyl having 7 to 13 carbons (especially benzyl), particularly preferably unsubstituted. , Fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methyl Sulfiel, methylsulfol, methoxymethyl, ethoxymethyl, methoxyethyl, aceethoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, Dimethylamino, dimethylaminomethyl, dimethylaminoethyl and amino are preferred.

As R ⁹ , hydrogen, alkyl having 1 to 5 carbon atoms, aryl, and benzyl are preferable, and hydrogen and methyl are particularly preferable.

[0022] As R ^1Q and R ¹¹ , R ^1Q and R ¹¹ are preferably -0-, or R ^1Q is hydrogen and R ¹¹ is preferably hydrogen, hydroxy or methoxy. Those which are -0- are preferred.

[0023] Pharmacologically preferred acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, lactate, and quaternary salt. Organic carboxylate such as acid salt, oxalate, glutarate, malate, tartrate, fumarate, mandelic acid, maleate, benzoate, phthalate, etc., methanesulfonate And organic sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate and the like. Among them, hydrochloride, hydrobromide, phosphate, tartar For which an acid salt or a methanesulfonate is preferably used. The present invention is not limited to these.

[0024] Among the compounds of the general formula (I) according to the present invention, -X- is a carbon chain having 2 carbon atoms which is a part of a ring structure, Y, Ζ is -C (= 0)-, and 2 A benzene condensed ring in which R ⁴ is unsubstituted or substituted with one or more R ⁵ , R ⁹ is hydrogen, and R ^1Q and R ¹¹ are bonded to each other to form a compound represented by the general formula (la). Table 1 shows specific examples of the compound. In the following table, CPM means cyclopropylmethyl, and the 6-position bond is α or β.

[0025]

[0026] Of the compounds of general formula (la), methyl R ¹ is cyclopropyl, is R ^2, R ³ force hydroxy, R 'is 4-Furuoro, the following compounds 6-position of the three-dimensional is 13

[0027] [Formula 4]

With N- [l 7- (cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxymorphinan-6β

-It is named 4-fluorophthalimide.

[0029] [Table 1-1] table 1

1-2] Table 1 (continued ^

1-3] Table 1 (continued;

H] Table 1 (continued

1-5] Table 1 (continued)

Among the compounds of the general formula (I) used in the present invention, -X- is a carbon chain having 3 carbon atoms which is a part of a ring structure, Y is -C (= 0)-, Z is a valence bond, 2 benzene fused ring number of R ⁴ is substituted with R ⁵ or more unsubstituted or one, R ⁹ is hydrogen, R ^10, R ¹¹ are bonded to - 0 Table below following general formula Ob) is a compound of Table 2 shows specific examples of the compound to be prepared. [0035] [Formula 5]

(lb)

[0036] In the compound of the general formula (lb), R ¹ is cyclopropylmethyl, R ² and R ³ are hydroxy, and R ⁵ is

The following compound, which is 6-fluoro and the stereo at position 6 is 13.

[0037] [Formula 6]

[0038] is converted to 2- [17- (cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxymorphinan-6β

-Yl] -6-fluoro-2,3-dihydro-isoindol-1-one.

[0039] [Table 2-1]

Table z

twenty two] Table 2 (continued)

twenty three] Table 2 (continued)

twenty four]

2-5] Table 2 (continued

2-6] Table 2 (continued)

Among the compounds of the general formula (I) used in the present invention, a carbon chain having 3 carbon atoms in which -X- is part of a ring structure (in which one carbon is replaced by a sulfur atom), Y, (= o)-, where z is a valence bond and four R ⁴ bonded to the same sulfur atom are two oxygen atoms A benzene condensed ring in which two R ⁴ are unsubstituted or substituted with one or more R ⁵ to form a group, is hydrogen, R ^1Q , and R ¹¹ are bonded to form -0- in the following general formula (Ic). Table 3 shows specific examples of the compounds represented.

[0046]

(1c)

[0047] Among the compounds of the general formula (Ic), the following compounds in which R ¹ is cyclopropylmethyl, R ² and R ³ are hydroxy, the benzene ring is unsubstituted, and the 6-position stereo is 13

[0048]

[0049] is named N- [17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl] -◦-sulfonebenzoic imide.

[0050] [Table 3-1]

Table 3

3-2] Table 3 (continued)

3-3] Table 3 (continued)

3-4] [s- ε 挲] [οο]

Sl0900 / S00rdf / X3d 2 9Z8 ^ 60 / S00∑: OAV Table 3

3-6] Table 3 {Sell)

CP H 0H (Unsubstituted)

CP H 0H 4-F

CPM H 0H 5-F

CPM H 0H 6-F

CPM H 0H 7-F

CPM H 0H 5, 6- F

CPM H 0H 4, 5, 6, G F

CPM H 0H 4-CI

GP H 0H 5-CI

CPM H 0H 6-CI

GPM H 0H 7-CI

GPM H 0H 5, 6-GI

CPM H 0H 4-Me

GPM H 0H 5-e

CPM H 0H 6- e

GPM H 0H 7- e

GPiS H 0H 5, 6-Me

CPM H 0H 4-O e

CPti H 0H 5-OMe

CPM H 0H 6-OMe

CPM H 07-OMe

CPM H 0H 5, 6-O e

Aryl H 0H (unsubstituted)

Aryl H 0H 4-F

Arinole H 0H 5-F

Aryl H 0H 6-F

Aryl ¹ H 0H 7-F

Aryl H 0H 5, 6-F

Aryl H 0H 4, 5, 6, 7— F

Aryl H 0H 4- CI

Peril H 0H 5 CI

Aryl H 0H 6 Gl

Aryl H 0H 7-CI

Peril H 0H 5, 6-CI

Aryl H 0H 4-Me

Aryl H 0H 5-Me

Aryl H 0H 6 Me

Aryl H 0H 7- Me

Aryl H 0H 5, 6-Me

Aryl H 0H 4-OMe

Aryl H 0H 5-OMe

Aryl H 0H 6-OMe

Aryl H 0H 7-OMe

Aryl H 0H 5, 6-OMe Of the compounds of the general formula (I) according to the present invention, -X- is a carbon chain having 2 carbon atoms which is a part of a ring structure, Y and Ζ are -C (= 0) -, A cyclohexene condensed ring in which two R ⁴ are unsubstituted or substituted by one or more R ⁵ , R ⁹ is hydrogen, and R ^1Q and R ¹¹ are bonded to form a compound of the general formula ( Id) Table 4 shows specific examples of the compound.

[0057] [Dani 9]

(1 d)

[0058] Further, among the compounds of the general formula (Id), the following compounds wherein R ¹ is cyclopropylmethyl, R ² and R ³ are hydroxy, cyclohexene ring is unsubstituted, and the 6-position stereo is 13 Compound

[0059] [Formula 10]

[0060] is converted to Ν-[(17-cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxymorphinan-6β

-Yl] -3,4,5,6-tetrahydrophthalimide.

[Table 4-1]

Table 4

4- 2] Table 4

Table 4-3] Table 4 (kneading)

4-4]

4-5] Table Sano

The morphinan derivative having a nitrogen-containing cyclic substituent and represented by the general formula (I) and used as an active ingredient of the antipruritic agent of the present invention can be specifically produced by the following method. Monkey

[0067] Among the compounds represented by the general formula (I) of the present invention, the compounds represented by the general formula (IA) (R ¹ , R ² ,

^{^{^{R 5, R 9, R 1Q}}} , R U is as defined above, the dotted line sulfonimide derivative cyclic imide or represented by representing) a single bond or an aromatic ring bonded, as shown in Scheme 1 Formula (Π) (, R ² ,

R ^9, R, 1 grade Amin body general formula R 1 ¹ is represented by the same) in the definition (III) (R ⁵ is an acid anhydride represented by the same) in the definition, or the general formula (m ') (R ² ° is an alkyl having 1 to 5 carbon atoms, and R ⁵ is the same as defined above). If necessary, the reaction can be carried out in the presence of an acid or a base in the reaction system.

[0068] [Formula 11]

()

[0069] The acid anhydride (111) and the sulfonic acid derivative (ΠΓ) are different from the primary amine compound (11, when R ³ is hydroxy, it may be protected with a suitable protecting group such as methoxymethyl). Although it is preferable to use 1 to 20 equivalents, it is possible to use 0.5 to 50 equivalents, and good results are obtained with 1 to 10 equivalents. Solvents include non-protonic polar solvents such as DMF, dimethylacetamide, and DMSO; ether solvents such as getyl ether, THF, DME, and dioxane; hydrocarbon solvents such as benzene, toluene, and xylene; dichloromethane; Halogen solvents such as chloroform and 1,2-dichloroethane, alcohol solvents such as methanol, ethanol, propanol and butanol, and acidic solvents such as acetic acid and propionic acid can be used. And closhol form is preferably used.

[0070] If necessary, bases to be co-existed include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and sodium acetate, and organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine. Among them, triethylamine, pyridine, potassium carbonate and sodium carbonate are preferably used. The base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, based on the substrate. On the other hand, as the acid, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, carboxylic acids such as acetic acid, propionic acid and benzoic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid can be used. Carboxylic acids such as acetic acid, propionic acid and benzoic acid, especially vinegar Acids are preferably used. The amount of the acid to be used is 1-30 equivalents, preferably 1-10 equivalents, relative to the substrate. However, a method in which acetic acid or the like is used as a solvent is also preferable. In this case, an excess acid will coexist.

[0071] The reaction can be carried out usually at a temperature in the range of -20 to 200 ° C, and preferably in the range of 0 to 150 ° C, satisfactory results can be obtained. The reaction time is appropriately selected according to the conditions such as the reaction temperature, but a satisfactory result is usually obtained with a 30 minute power and about 30 hours. The concentration of the substrate (II) in the reaction system is not particularly limited, but is usually preferably about 1 mmol / L to 1 mol / L.

The primary amine compound represented by the general formula (Π) used as a starting material in Scheme 1 is

20, 1100 (1977), and J. Org. Chem. 45, 3366 (1980).

[0073] The general formula (IA)

^{^{^{R 2, R 3, R 5}}} , R 9, R 1Q, inner cyclic imide derivatives of compounds is R ^U is represented by the same) in the definition, the Mitsunobu reaction described in Tetrahedron. 50, 9757 (1994) It can be manufactured in any way.

The general formula (I) according to the present invention, wherein Y is -C (= 0)-and Z is a valence bond (IB) (R ¹ ,

The cyclic amide form of R ⁴ , R ⁹ , R ^1Q , R ^U , k, and X is the same as defined above is represented by the general formula (IV R ² ,

R ⁹ , R ^1Q , R ^U , k, X are the same as defined above, and L is chlorine, bromine, iodine, or OTs, OMs) or

R ⁴ , R ⁹ , R ^1Q , R ^U , k, and X are the same as defined above, and chlorine is chlorine or OR ¹² (where R ¹² is hydrogen, alkoxy having 1 to 5 carbons, 7 to 13 carbons). Which represents an alkanoyloxy having 1 to 5 carbon atoms) by an intramolecular conversion reaction using a general alkylidation reaction of an amide group or an aminodination reaction of an amino group. it can. The compounds represented by the general formulas (IV) and (V) used as starting materials in Scheme 2 can be obtained by the method described in WO 93/15081 or the like. [0075] [Formula 12]

(V)

Scheme 2

[0076] Alkylation or amidation can be performed by a commonly used method in which a base coexists in a solvent.

[0077] Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide and potassium t-butoxide. Organic bases such as metal alkoxides, triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, based on the substrate. However, in the case of the amidation reaction, satisfactory results may be obtained without using a base.

[0078] Examples of the solvent include aprotic polar solvents such as DMF, dimethylacetamide, and DMSO; ether solvents such as dimethyl ether, THF, DME, and dioxane; hydrocarbon solvents such as benzene and toluene; dichloromethane; Halogen solvents such as chloroform and 1,2-dichloroethane can be used, and among them, DMF, THF and toluene are preferably used. Satisfactory results can be obtained at a reaction temperature of usually -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is appropriately selected according to conditions such as the reaction temperature, but a satisfactory result is usually obtained in about 30 minutes to 100 hours. The concentration of substrate (IV) and (V) in the reaction system Is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.

[0079] The general formula (I) of the present invention

R ^1Q , R ^U , X, Y, Z, and k are the same as defined above), wherein Y is -C (= 0)-, a general formula (ID) and (IE)

R ^1Q , R ^U , X, and Z are the same as defined above, and R ¹³ represents alkyl having 1 to 5 carbons and aralkyl having 7 to 13 carbons). By the method of the general formula (IC R ¹ , R ² ,

R ^U , X and Z are the same as defined above), and can be produced by alkylation or acylation in a solvent in the presence of a base. Note that the compound represented by the general formula (IC) used as a starting material in Scheme 3 can be obtained by the methods shown in Schemes 1 and 2.

[0080]

(I E)

Scheme 3

[0081] It is preferable to use 1 to 20 equivalents of the alkylating agent or the acylating agent, and a satisfactory result can be obtained with 1 to 10 equivalents.

[0082] As the base, an organic lithium reactant such as methyllithium, butyllithium, or LDA; a metal hydride such as sodium hydride or potassium hydride; or a metal alkoxide such as sodium ethoxide or potassium t-butoxide is used. Among these, LDA and butyllithium are preferably used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, based on the substrate. [0083] Examples of the solvent include aprotic polar solvents such as DMF, dimethylacetamide, and DMSO; ether solvents such as dimethyl ether, THF, DME, and dioxane; and hydrocarbons such as pentane, hexane, benzene, and toluene. A system solvent can be used, and among them, THF and DME are preferably used.

[0084] Satisfactory results can be obtained at a reaction temperature of usually -100 to 200 ° C, preferably -80 to 150 ° C. The reaction time is appropriately selected depending on conditions such as the reaction temperature, but a satisfactory result is usually obtained in 30 minutes to 30 hours. The concentration of the substrate (IC) in the reaction system is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.

[0085] Among the compounds represented by the general formula (I), the general formula (IG) wherein R ³ is hydroxy (wherein formulas ¹ , ² and

R ⁹ , R ^1Q , R ^U , X, Y, Z, and k are the same as defined above) when synthesizing a compound represented by the general formula wherein R ³ is methoxy for the purpose of protecting the phenol portion. (IF) (wherein, R ¹ , R ² , R ⁴ , R ⁹ , R ^1Q , R ^U , X, Y, Z, and k are the same as defined above). As shown in Scheme 4 below, the deprotection at this time is a general demethylation reaction of phenolic methyl ether, specifically, (1) a method using boron tribromide, or (2) a basic method using boron tribromide. Under the conditions, the method can be carried out with a deviation from the method using an alkyl thiol.

[0086] [Formula 14]

(IF) (IG)

In the method (1), satisfactory results can be obtained with 1 to 7 equivalents of boron tribromide, although 1 to 20 equivalents are preferred. As the reaction solvent, dichloromethane is preferable among halogen-based solvents such as dichloromethane, chloroform and 1,2-dichloroethane. Satisfactory results can be obtained at a reaction temperature of -50 to 40 ° C even though a reaction temperature of -70 to 50 ° C is preferred. Reaction times of 10 minutes to 10 hours are preferred, and satisfactory results are obtained in 30 minutes to 5 hours. Also the reaction The concentration of the compound represented by the general formula (IF) in the system is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.

[0088] In the method (2), propanethiol is preferably used among alkylthiols such as ethanethiol, propanethiol, and butanethiol as a reactant. Satisfactory results are obtained with 1 to 7 equivalents, although 1 to 20 equivalents are preferred. As a base, potassium t-butoxide, sodium hydride, potassium hydride and the like are preferable, and potassium t-butoxide is preferably used. Satisfactory results are obtained with 1 to 7 equivalents, although 1 to 20 equivalents are preferred. The reaction solvent is preferably an aprotic polar solvent such as DMF or dimethylacetamide, or an ether-based solvent such as THF or DME. Among them, DMF which is an aprotic solvent is preferably used. Satisfactory results can be obtained at a reaction temperature of 80 to 150 ° C, although a reaction temperature of 50 to 200 ° C is preferred. Satisfactory results are obtained with reaction times of 2 to 8 hours, although 1 to 15 hours are preferred. The concentration of the compound represented by the general formula (IF) in the reaction system is not particularly limited, but is usually preferably 1 mmol / L to 1 mol / L.

[0089] The effectiveness of the morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) for pruritus is confirmed by showing an action of suppressing an attracting behavior in animals. be able to. The effect of suppressing the punishing behavior in animals can be confirmed by the method described in a previously reported literature [Eur. J. Pharmacol, vol 477, 29-35 (2003)], but it is not always necessary. It is not limited to this method.

[0090] The antipruritic agent of the present invention may be used for skin diseases such as atopic dermatitis, neurogenic dermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, Senile skin Itching, insect bites, photosensitivity, juniper, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies, acne vulgaris, etc. It is also used for visceral disease or medical treatment accompanied by, for example, malignancy, diabetes, liver disease, renal failure, renal dialysis, gout, thyroid disease, blood disease, iron deficiency and the like. In addition, the treatment of pregnancy, parasitic infections, and occasionally pruritus perceived for drug or psychogenic reasons are also within the scope of the present invention. Furthermore, it can be applied to itching associated with ophthalmology and ENT diseases. The antipruritic agent of the present invention may be used in mammals (for example, mice, rats, wild, muster, egrets, cats, dogs, dogs, higgies, monkeys, and humans). Can do.

[0091] In the antipruritic agent of the present invention, the compound of the present invention is used alone, or for treating or preventing a disease, or for reducing or suppressing symptoms. It can be administered in combination with one or more substances. Examples of such substances include anthelmintic agents such as fipronil, lufenuron, imidacloprid, avenolemectins (eg avermectins), aibamectin, doramectin ( doramectin)), milbemycins, organophosphates, pyrethroids; antihistamines, such as chlorphen-lamin, trimeprazine, diphenhydramine, doxylamine; antifungals, such as fluconazole, ketoconazole, itraconazole (Itraconazole), griseofulvin, amphotericin B; antibacterial drugs, for example, enrofloxacin, manolevofloxacin, ampicillin, amoxicillin; anti-inflammatory drugs, for example, prednisolone, betamethasone, carprofen fen (carprofen) ), Clobetasol, diflorasone, hydroconoretisone, dexamethasone, dexamethasone, ketoprofen, meloxicam; antiallergic drugs, such as mequitazine, kequitifen (mequitazine) ketotifen), azelastine, oxatomide, fexofenadine; drugs for treating atopic dermatitis, for example, tacrolimus; supplements, for example, γ-linoleic acid; emollients; And humectants, which are provided by way of example and should not be construed as limiting.

[0092] When the antipruritic agent of the present invention is used clinically, the drug may be a free base or a salt thereof, and may be excipients, stabilizers, preservatives, buffers, solubilizing agents, emulsifiers. Additives such as a diluent and a tonicity agent may be appropriately mixed. Dosage forms include tablets and capsules, granules, powders, syrups and other oral preparations, injections, suppositories, liquids and other parenteral preparations, ointments, creams, patches, and other topical preparations. Administration and the like. External preparations are particularly preferred for treating skin diseases. External preparations include fats and oils (preferably vegetable oils, animal oils, waxes, fatty acids, fatty alcohols, mineral oils, turpentine oil, petrolatum, etc.), solvents (preferably water, ethanol, glycerin, propylene glycol, isopropyl alcohol, ethers, etc.), Preservative (preferably paraoxybenzoate, benzoate Acid, salicylic acid, sorbic acid, benzalco-pam, benzet-pom, propylene glycol, chlorobutanol, benzyl alcohol, ethanol, etc., stabilizers (preferably tocopherol, butylhydroxyethanol, dibutylhydroxytoluene, sulfite) , Disodium edetate, etc.), anionic surfactants (preferably potash stone, medicinal stone, zinc desilate, calcium stearate, magnesium stearate, aluminum monostearate, calcium linoleate, Non-ionic surfactants (preferably glyceryl monostearate, sorbitan fatty acid partial esters, sucrose fatty acid esters, polyoxyl 40 stearate, macrogol, lauromacrogol, polyoxyethylene) 160, Lioxypropylene 30 glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid partial esters, etc.), and cationic surfactants (preferably, Shirazidani Benzalcodium, Shiridani Benzetonium, Salt) Dandelion cetyl pyridinium, etc.), powders (preferably, zinc oxide zinc, zinc white starch, kaolin, bismuth subnitrate, titanium oxide, titanium dioxide, titanium dioxide, carboxylic anhydride, talc, etc.), preservatives (preferably para Benzoic acid esters, sorbic acid, p-chloro-m-xylenol, Irgasan, hexachlorophene, etc.), emulsifiers (preferably gum arabic, tragacanth, bentonite, sodium carboxymethylcellulose, methylcellulose), wetting agents ( Preferably glycerin, propylene glycol, polyethylene glycol , 1,3-butylene glycol, sorbitol, sodium polypyrrolidonecarboxylate, sodium lactate, sodium hyaluronate, chitin derivatives, urea, amino acids, sugar amino acids, etc.) to form a base, ointments, creams, compresses In addition to preparing agents, coatings, patches and the like, they can also be used as external solutions. Also, for ophthalmic use, it can be prepared as eye drops.

[0093] The antipruritic agent of the present invention desirably contains the above active ingredient in an amount of 0.00001 to 90% by weight, more preferably 0.0001 to 70% by weight. The amount to be used is appropriately selected according to symptoms, age, body weight, administration method, etc., but for adults, injections and external preparations, 0.1 g to lg of active ingredient per day, oral In this case, the dose is 1 μg to 10 g, which can be administered once or in several divided doses.

[0094] Hereinafter, the present invention will be described specifically with reference to Examples.

Example [0095] Reference Example 1

Synthesis of N-[(17-cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxy-morphinan-6β-yl] -phthalimide hydrochloride (Compound II)

[0096] [Formula 15]

[0097] 150 mg (0.44 mmol) of 6β-naltrexamine was dissolved in 7 mL of DMF, and 71 mg (0.48 mmol) of phthalic anhydride and 0.92 mL (0.66 mmol) of triethylamine were added and the mixture was stirred at 140 ° C for 4 hours. Stirred. The reaction solution was allowed to cool to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 120 mg of free form β (yield 58%). A part of this was used as a hydrochloride to obtain Titlei-Danigo.

[0098] ^J H-NMR (ppm) (300 MHz, CDC1)

Three

7.8-7.9 (2H, m), 7.7-7.8 (2H, m), 6.76 (1H, d, J = 7.9 Hz), 6.63 (1H, d, J = 8.2 Hz), 5.18 (1H, d, J = 8.5 Hz), 4.0--4.1 (1H, m), 3.11 (1H, d, J = 5.6 Hz), 3.05 (1H, d, J = 18.8 Hz), 2.6-2.9 (3H, m), 2.3--2.4 ( 3H, m), 2.15 (1H, dt, J = 12.0, 3.5 Hz), 1.4-1.7 (4H, m), 0.8-0.9 (1H, m), 0.5--0.6 (2H, m), 0.1--0.2 ( 2H, m) (free) IR (cm— (KBr)

3320, 1769, 1708, 1626, 1504, 1466, 1428, 1379, 1323, 1271, 1240, 1190, 1173, 1075

Elemental analysis value

Formula: C28H28N2O5-1.0 HCM .O H20

Calculated values: C: 63.81, H: 5.93, N: 5.32, Cl: 6.73

Obtained: C: 63.72, H: 6.03, N: 5.40, Cl: 6.49 Mass (EI): 472 (M +)

[0099] Reference Example 2

Synthesis of N-[(17-aryl) -4,5a-epoxy-3,14-dihydroxy-morphinan-6β-yl] -phthalimido tartrate (Compound 2)

[0100] [Formula 16]

According to the method described in Reference Example 1, using 6β-naloxamine instead of 6β-naltrexamine, 24 mg (yield 34%) of the free form of title compound 2 was obtained. This was used as the tartrate salt to give the title compound 2.

[0102] ^J H-NMR (ppm) (300 MHz, CDC1)

Three

7.75-7.8 (2H, m), 7.6-7.7 (2H, m), 6.72 (IH, d, J = 8.2 Hz), 6.59 (IH, d, J = 8.2 Hz), 5.7-5.8 (IH, m) , 5.1—5.2 (3H, m), 4.0—4.05 (IH, m), 3.0—3.1 (3H, m), 2.45-2.9 (5H, m), 2.0-2.3 (2H, m), 1.6—1.7 ( IH, m), 1.4-1.5 (2H, m) (free)

Mass (ESI): 459 (M ⁺ +1)

[0103] Reference Example 3

N-[(17-cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxy-morphinan-6β-yl] -3,4,5,6-tetrahydrophthalimide'tartrate Synthesis of things

[0104] [Formula 17]

[0105] 6 β-naltrexamine 113 mg (0.33 mmol) was dissolved in chloroform 3.3 mL, 58 mg (0.38 mmol) of 3,4,5,6-tetrahydrophthalic anhydride and 114 μL (0.82 mmol) of triethylamine were added and stirred at room temperature for 50 minutes. Thereafter, 234 μL (1.68 mmol) of triethylamine and 158 μL (1.68 mmol) of acetic anhydride were added to the reaction solution, and the mixture was heated under reflux for 1 hour. Thereafter, the reaction mixture was allowed to cool to room temperature, and the reaction mixture was concentrated with an evaporator. Then, 3 mL of methanol and 300 μL of 28% aqueous ammonia were added, and the mixture was stirred at room temperature for 4 hours. Thereafter, water was added to the reaction solution, and the mixture was extracted with black-mouthed form. The organic layers were combined, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 121 mg (yield 77%) of a free form of the title compound. This was used as the methanesulfonate to give the title compound.

[0106] ^J H-NMR (ppm) (300 MHz, CDC1)

Three

0.12 (2H, m), 0.52 (2H, m), 0.84 (1H, m), 1.43 (3H, m), 1.65 (1H, m), 1.76 (4H, br), 2.12 (3H, td, J = 12.0, 3.6 Hz), 2.26-2.38 (7H, m), 2.63 (3H, m), 3.03 (1H, d, J = 18.4 Hz), 3.08 (1H, d, J = 5.6 Hz), 3.83 (1H, ddd, J = 13.2, 8.4, 3.6 Hz), 5.05 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 8.4 Hz) (free form)

Mass (ESI): 477 (M ⁺ +1)

[0107] Reference Example 4

[N- (17-Cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxy-morphinan-6β-yl] -0-sulfonbenzoic acid imide 'Synthesis of tartaric acid salt

[0108] [Formula 18]

6 β-Amino- (17-cyclopropylmethyl) -4,5a-epoxy-3-methoxymethoxy-morphin-14-ol 203 mg (0.53 mmol) was dissolved in 10 mL of chloroform at 0 ° C. Then, 0.15 mL of triethylamine and 136 mg of methyl- (2-chlorosulfol) -benzoate were added thereto, and the mixture was stirred at room temperature for 8 hours, and then heated to reflux for 30 minutes. Allow the reaction to cool to room temperature, A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography.

2-[(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -sulfamoyl] -benzoic acid methyl ester 219 mg (71% yield) ).

[0110] The obtained 2-[(17-cyclopropylmethyl-4,5a-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6j8-yl) -sulfamoyl] -benzoic acid methyl ester 91 mg (0.16 mmol) was dissolved in 10 mL of DMF, 352 mg of potassium carbonate was added, and the mixture was stirred at 80 ° C for 3 hours. After allowing the reaction mixture to cool to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated to give N-[(17-cyclopropylmethyl) -4,5a-epoxy-14-hydroxy- as a crude product. 3-methoxymethoxy-morphinan-6β-yl] -0-sulfonbenzoic imide was obtained.

[0111] The obtained crude product was dissolved in 2-mL of 2-propanol and 2 mL of chloroform, and 0.2 mL of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 13 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 67 mg (yield 85%: 2steps) of a free form of the title compound. This was used as the tartaric acid salt to obtain the title compound 4.

[0112] ^J H-NMR (ppm) (300 MHz, CDC1)

Three

8.06-8.08 (m, 1H), 7.82-7.97 (m, 3H), 6.80 (d, 1H, J = 8.1 Hz), 6.65 (d, 1H, J = 8.1 Hz), 5.28 (d, 1H, J = 8.3 Hz), 3.92 (ddd, 1H, J = 3.9, 8.3, 13.1 Hz), 3.11 (d, 1H, J = 5.6 Hz), 3.06 (d, 1H, J = 18.3 Hz), 2.78-2.87 (m, 1H), 2.60-2.70 (m, 2H), 2.32-2.39 (m, 3H), 2.13-2.20 (m, 1H), 1.46-1.76 (m, 4H), 0.82-0.88 (m, 1H), 0.52- 0.57 (m, 2H), 0.12-0.15 (m, 2H) (free body)

Mass (ESI): 509 (M + + l)

[0113] Reference Example 5

2-[(17-cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxy-morphinan-6β-yl] -2,3-dihydro-isoindol-1-one'tartrate Synthesis of daggers [0114] [Formula 19]

[0115] N-[(17-cyclopropylmethyl) -4,5a-epoxy produced by the method described in Reference Example 1

-3,14-dihydroxy-morphinan-6j8-yl] -phthalimide (156 mg, 0.33 mmol) was dissolved in a mixed solution of 5 mL of methanol and 5 mL of chloroform, and 61 mg (1.61 mmol) of sodium borohydride was dissolved. ) Was added at 0 ° C, and the mixture was stirred for 2 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and 2-[(17-cyclopropylmethyl) -4,5a-epoxy-3,14-dihydroxy-morphinan-6β-yl]- 130 mg (83% yield) of 3-hydroxy-2,3-dihydro-isoindol-1-one (a mixture of diastereomers) was obtained.

[0116] 150 mg (0.32 mmol) of the obtained purified product was dissolved in a mixed solution of 7 mL of methylene chloride and 25 mL of chloroform, and 0.22 mL (1.73 mmol) of boron trifluoride etherate, 0.28 mL of triethyl silane (1.73 mmol) was stirred at 0 ° C and stirred for 22 hours. Thereafter, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to give 55 mg (yield 38%) of a free form of the title compound. This was used as the tartrate salt to obtain the title compound.

[0117] 1H-NMR (ppm) (300 MHz, CDC1)

Three

7.85 (d, J = 8.2 Hz, 1H), 7.58-7.45 (m, 3H), 6.79 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 4.68 (d, J = 8.2 Hz, 1H), 4.52 (d, J = 16.8 Hz, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.27 (ddd, J = 12.6, 8.2, 4.4 Hz, 1H), 3.11 (d , J = 5.5 Hz, 1H), 3.06 (d, J = 18.4 Hz, 1H), 2.70-2.59 (m, 2H), 2.39 (d, J = 6.6 Hz, 2H), 2.31-2.12 (m, 3H) , 1.72-1.49 (m, 4H), 0.93-0.79 (m, 1H), 0.58-0.50 (m, 2H), 0.17-0.11 (m, 2H) (free One)

IR (cm— (KBr)

3075, 3004, 2925, 2818, 1658, 1622, 1498, 1455, 1377, 1330, 1307, 1279, 1228, 1188, 1153, 1117, 1069, 1051,, 1034, 981, 943, 919, 884, 859, 740

Mass (EI): 458 (M +)

[0118] Reference Example 6

Synthesis of 17-cyclopropylmethyl-4,5a-epoxy-3,14-dihydroxy-6β- (Ν-methylbenzamido) morphinanhydrochloride

[0119] [Formula 20]

[0120] 194 mg (0.54 mmol) of 17-cyclopropylmethyl-4,5a-epoxy-3,14-dihydroxy-6β-methylaminomorphinan was dissolved in 5 mL of chloroform and 0.16 mL (1.11 mmol) of triethylamine. And 0.13 mL (1.09 mmol) of benzoyl chloride were added, and the mixture was stirred at room temperature for 1 hour. Then, 5 mL of methanol and 1.5 mL of 2N NaOH aqueous solution were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Thereafter, water was added to the reaction mixture, and the mixture was extracted with black-mouthed form. The organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 237 mg (yield 95%) of a free form of the title compound X. This was used as the hydrochloride salt to obtain the title compound Z.

[0121] ^J H-NMR (ppm) (400 MHz, DMSO—d6)

7.4-7.2 (m, 5H), 6.65 (d, J = 8.1 Hz, IH), 6.50 (d, J = 8.1 Hz, IH), 4.94 (d, J = 8.0 Hz, IH), 3.74 (m, IH ), 3.3--3.1 (m, 2H), 3.03 (s, 3H), 3.0--2.8 (m, 4H), 2.5--2.3 (m, IH), 2.2-2.1 (m, IH), 1.65-1.55 (m , IH), 1.45-1.35 (m, 2H), 1.3-1.2 (m, IH), 1.1-0.9 (m, 2H), 0.7--0.3 (m, 4H) Mass (ESI): 461 (M + 1 +)

[0122] Example 1

Substance-P-induced drag behavior suppression effect

Male ddY mice were received at 4 weeks of age, preliminarily reared, and used at 5 weeks of age. On the day before the experiment, the rostral back of the mouse was shaved using a clipper. Each compound was dissolved in 10% DMSO. Either the test drug or the vehicle is administered subcutaneously on the rostral back of the mouse, and 30 minutes later, 50-μL of substance-P (250 nmom / site) dissolved in PBS (Phospahte Buffered Saline) is applied to the hair removal site. Was administered intradermally. Immediately afterwards, they were placed in observation cages (10 * 14 * 22 cm), and the behavior for the next 30 minutes was photographed with a video camera in an unmanned environment. The video was played, and the number of times the mouse pulled the hind limb near the substance-P administration site was counted. The experiment was performed with 8 animals per group. If there is a statistically significant difference between the mean number of pulls in the vehicle administration group and the mean number of pulls in the test drug administration group, it is determined that there is an antipruritic effect. The dose was shown to be the dose that halved the number of pulls in the group (Table 5).

[0123] [Table 5]

Industrial applicability

Since the antipruritic agent of the present invention has an excellent antipruritic effect and has few side effects, it is useful for treating pruritus associated with various diseases.

Claims

Claims General formula 0)

[Chemical 1]

(I)

[Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkylalkyl having 6 to 8 carbons, aryl having 6 to 12 carbons, 13 aralkyl, 3 to 7 carbon atoms, fulleralkyl (alkyl moiety has 1 to 5 carbon atoms), chenylalkyl (alkyl moiety has 1 to 5 carbon atoms), or pyridylalkyl (alkyl moiety Represents 1 to 5);

Υ, Ζ independently represent a valence bond or -C (= 0) _;

-X- is a carbon chain of 2 to 7 carbon atoms that becomes part of the ring structure (unsaturated in carbon chains in which one or more carbon atoms may be replaced by nitrogen, oxygen, or sulfur atoms) Contains a bond, which may represent);

k represents an integer from 0 to 8;

2 2 p 2 p 2 p

K R ^{4 s} force representing COR ⁶ , SO NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH) NR ⁷ R ⁸ , (CH) N (R ⁷ ) COR ⁸ Chi, the same two R ⁴ an oxygen atom and is carbonyl group or a sulfoxide group Ghats attached to a carbon atom or a sulfur atom, and two R ⁴ Ghats sulfur atoms attached to the same carbon atom Two thiocarbonyl groups are substituted by four R ⁴ forces ^ oxygen atoms bonded to the same sulfur atom to represent a sulfone group, or substituted by adjacent carbons among k R ⁴ Benzene condensed ring, pyridine condensed ring, naphthalene condensed ring, cyclopropane condensed ring, cyclobutane condensed ring, cyclopentane condensed ring, cyclopentane condensed ring, unsubstituted or substituted with one or more substituents R ⁵ together with R ⁴ Represents a condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring, and R ⁵ is each independently fluorine, chlorine, bromine, iodine, nitro, , Hydroxy, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, trifluoromethyl, trifluoromethoxy, siryl having 6 to 12 carbons, isothiocyanato, SR ⁶ , SOR ⁶ , SOR ⁶ , (CH) OR ⁶ , (CH

2 2 p

2 p 2 p 2 2 2 p 2 p

2p2p2 represents;

2

p represents an integer from 0 to 5;

R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, alkyl having 3 to 7 carbons, aryl having 6 to 12 carbons, or aralkyl having 7 to 13 carbons;

RR ⁸ independently represents hydrogen, alkyl having 1 to 5 carbons, or aralkyl having 7 to 13 carbons, and the general formula (I) includes a (+) form, a (-) form, and a (f) form An antipruritic agent comprising, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent represented by the formula [I] or a pharmacologically acceptable acid addition salt thereof.

2. The pruritus according to claim 1, wherein, in the general formula (I), X is a carbon chain having 2 to 7 carbon atoms which forms a part of a ring structure (however, the carbon chain may contain an unsaturated bond). Agent.

[3] The antipruritic agent according to claim 1 or 2, wherein in formula (I), Y is -C (= 0)-and Z is a valence bond.

[4] The antipruritic according to claim 1 or 2, wherein in formula (I), Y and 、 are both -C (= 0)-.

[5] In the general formula (I), R ¹ is hydrogen, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkylalkyl having 6 carbon atoms, arylalkyl having 6 to 12 carbon atoms, or cycloalkyl having 6 to 12 carbon atoms. alkenyl, such two R ⁴ to replace each carbon adjacent together connexion unsubstituted or 1 or more benzene fused ring which is substituted with a substituent R ^5, pyridine fused ring, naphthalate Ren fused ring, cyclopropane 5. The antipruritic agent according to claim 4, which forms a condensed ring, a cyclobutane condensed ring, a cyclopentane condensed ring, a cyclopentene condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring.

[6] In the general formula (I), R ¹ is hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, aryl, or preyl, and R ² and R ³ are hydrogen, hydroxy , Methoxy, ethoxy, aryloxy, benzyloxy, acetoxy or propionoxy, k is 2 and two R ⁴ are taken together and are unsubstituted or substituted with 1 to 4 substituents R ⁵ R ⁵ is independently fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoro. methyl, triflumizole Ruo b methoxy, Xia Nyufu Eniru, ^{^{isothiocyanato, SR 6, SOR 6, SO}} R 6, (CH) 0R 6, (CH) COR 6, (CH) CO R 6

2 2 p 2 p 2 p 2

^{^{, SO NR 7 R 8, CONR}} 7 R 8, (CH) NR 7 R 8 or ^{(CH) N (R 7)} , a COR ^8, R ⁶ is hydrogen, main

2 2 p 2 p

Chill, Echiru, propyl or Hue, - a le, RR ⁸ are each independently hydrogen, methylation, a Echiru, propyl or base, Njiru a R ⁹ force hydrogen or methyl,, R ^1Q, R ¹¹ 5. The antipruritic agent according to claim 4, wherein R ^1Q is hydrogen, and R ¹¹ is hydrogen, hydroxy, or methoxy.

[7] In the general formula (I), R ¹ is hydrogen, cyclopropylmethyl, cyclobutylmethyl, or aryl, and R ² and R ³ are each independently hydrogen, hydroxy, methoxy, or acetate. Wherein k is 2 and two R ⁴ are together a unsubstituted or substituted benzene or cyclohexene fused ring with 1 to 4 substituents R ⁵ , R ⁵ is each independently fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy , Methoxy, ethoxy, triflumizole Ruo Russia methyl, triflumizole Ruo b methoxy, Xia input phenyl, Isochi ^{^{Oshianato, SR 6, SOR 6, SO}} R 6, (CH) OR 6, (CH) COR 6, (CH) CO R 6 , SO NR ⁷ R ⁸ ,

2 2 p 2 p 2 p 2 2

CONR ⁷ R ⁸ , (CH) NR ⁷ R ⁸ , or (CH) N (R ⁷ ) COR ⁸ , wherein R ⁶ is hydrogen, methyl, ethyl

2 p 2 p

R ⁷ , R ⁸ are each independently hydrogen, methyl, ethyl, propyl, or benzyl; R ⁹ is hydrogen or methyl; R ^1Q , R ¹¹ is 5. The antipruritic according to claim 4, which is bound to -0-.

[8] A method for producing an antipruritic agent of the morphinan derivative having a nitrogen-containing cyclic substituent or the pharmacologically acceptable acid addition salt thereof according to claim 1 or 7, Use for.

[9] The morphinan derivative having a nitrogen-containing cyclic substituent according to any one of claims 1 and 7, and one or more of pharmaceutically acceptable acid addition salts thereof. An antipruritic method comprising administering an effective amount to a patient.